Two-part capsule to accept pharmaceutical preparations for powder inhalers

ABSTRACT

The present invention relates to capsules for holding pharmaceutical preparations for powder inhalers with increased drug safety and capsules for pharmaceutical preparations for powder inhalers with improved adaptation to their use in powder inhalers. The capsules consist of water-insoluble hydrophobic synthetic materials which do not significantly affect the pharmaceutical quality of the contents themselves, but which improve the usability of the filled capsules with regard to their function, their longevity and/or the geographic location of their use, and are advantageous at various stages from manufacture up to utilisation.

[0001] The invention relates to new two-part capsules for holdingpharmaceutical preparations for use in powder inhalers.

THE PRIOR ART

[0002] Capsules with pharmaceutical preparations are often used in thetherapy and diagnosis of illnesses. The capsules can be orallyadministered or are used in certain medical apparatus such as powderinhalers. Generally, the capsules consist of two parts, a capsule body(body) and a capsule cap (cap), which are pushed togethertelescopically. However, multi-part capsules are also known. Thecapsules generally consist of gelatine, especially hard gelatine. In thecase of some special applications, the capsules occasionally consist ofwater-soluble synthetic materials easily digested by humans, in orderfor example to release the active ingredients in certain compartments ofthe gastrointestinal tract in the case of oral administration. Examplesof various capsule materials are listed hereinafter.

[0003] EP 0143524 discloses a two-part capsule of material which iseasily digestible by humans, preferably gelatine.

[0004] EP 0460921 describes capsules of chitosan and starch, grainpowder, oligosaccharides, methacrylic acid-methylacrylate, methacrylicacid-ethylacrylate, hydroxypropylmethylcelluloseacetate, -succinate or-phthaleate. The capsule material is distinguished by the contents notbeing released until they reach the large intestine.

[0005] GB 938828 discloses capsules for radioactive substances used intherapy or diagnosis. The capsules comprise water-soluble gelatine,methylcellulose, polyvinylalcohol or water-soluble non-toxicthermoplasts.

[0006] The materials which are used are often not very resistant to airhumidity, which is why the pharmaceutical quality of the contents cannotbe guaranteed for all climatic zones. Especially in climatic zone 4 (30°C./70% relative air humidity), conventional capsules cannot be used.

[0007] Two-part capsules, which are specially adapted for use in powderinhalers without necessarily being subjected to the conditions for oraladministration, are previously not known in the prior art. The capsulesfor powder inhalers comprise the same materials as are used for oraladministration, usually hard gelatine. However, these materials are notspecially perfected for use in powder inhalers.

[0008] One of the objectives of the present invention is to providecapsules which can be better adapted to the special conditions in powderinhalers.

[0009] The capsules which have hitherto been used in powder inhalershave various disadvantages as a result of their composition. Hencematerials used in construction of the capsules can alter theircharacteristics dependent on the ambient air humidity and/or do notalways have sufficient inherent stability. As a result, such a capsulecannot for example be used in climatic zone 4 as a result of the highair humidity, since the capsule material absorbs the humidity to such adegree that the inherent stability is seriously affected and/or thehumidity penetrates into the interior of the capsule. This has anegative effect on the pharmaceutical quality of the capsule's contents.The said materials also have diverse disadvantages in other variousstages in the life of the capsule from manufacturing up to utilisation,which affect the suitability of the capsule as a carrier forpharmaceutical preparations, the manner of administration of thecontents, the perishability of the contents and/or the usability of thecapsule in certain countries. A further disadvantage of conventionalcapsule materials is that e.g. they tend to bind powder materials tothemselves, especially when coated with a mould release agent which isoften necessary for production of the capsule. In the case of capsulesfor inhalation purposes, this leads to difficulty in accurately meteringthe fine fraction which is to enter the lungs.

[0010] A further objective of the present invention is to providecapsules for powder inhalers which do not have the aforementionedproblems of conventional capsules.

DESCRIPTION OF THE INVENTION

[0011] The present invention relates to a capsule for holdingpharmaceutical preparations for powder inhalers with increased drugsafety and capsules for pharmaceutical preparations for powder inhalerswith improved adaptation to use in powder inhalers. The capsules consistof water-insoluble, hydrophobic synthetic materials, which do notthemselves substantially influence the pharmaceutical quality of thecontents, but which improve the usability of the filled capsules withregard to their function, their longevity and/or the climatic zone, andare advantageous at various stages from production through toutilisation.

[0012] The capsules, according to the invention, consist of two parts, acapsule body (body) and a capsule cap (cap), which can be connectedtogether so as to form a stable enclosed hollow space of defined volumewhich contains the pharmaceutical formulation. The dimensions of thecapsule are chosen so that the capsule can be used with common powderinhalers which are used with capsules, such as those described forexample in patent documents DE 33 45 722 (Inhaler Ingelheim M), EP 0 591136 (Inhaler Ingelheim) or in the published German application DE 43 18455 (“HandiHaler®”).

DETAILED DESCRIPTION OF THE INVENTION

[0013] In one embodiment, the synthetic material of the capsule is notdigestible by humans, so that the active ingredient is not released whenthe capsule is taken orally. This has the advantage that inadvertentswallowing of the capsule cannot lead to a detrimental effect on health.This applies especially to small children or older people.

[0014] Preferably, synthetic materials are used which can be processedusing injection moulding or blow casting and/or synthetic materialswhere no mould release agent is necessary for their processing intocapsule caps or capsule bodies, which can cause adhesion of the contentsto the capsule wall. This has the advantage that the interior of the capor the body need not be cleaned from mould separation agent, in orderfor example to meet the official requirements (e.g. according to DAB(Deutsches Apotheker Buch)), which restricts the use of mould releaseagents for primary packaging means.

[0015] In a preferred embodiment of the invention, the syntheticmaterial does not exhibit any pronounced adhesion forpharmaceutical-chemical materials, especially for particles oflung-accessible size, so that when the capsule is used in one of theaforementioned inhalers, the entire contents of the capsule can bereleased. This has the advantage that exact dosage, especially of thelung-accessible fine fraction, is possible.

[0016] In a further embodiment, the capsule consists of a syntheticmaterial with a Shore hardness D of 65 to 73. A synthetic material ofthis hardness does not shatter when it is pierced or cut open, but atthe same time it is rigid enough so that the resulting hole does notclose up again. The advantage of such material is that no fragments canbe forced out of the capsule during opening, piercing or slicing open ofthe capsule in the powder inhaler which can be breathed in duringinhalation.

[0017] In one embodiment, the synthetic material capsule is so stablethat it can withstand a force along its longitudinal axis or transverseaxis of up to 15 N. The advantage of this is that the capsule is betteradapted to the stress which acts upon it during manufacture, filling,packaging, transportation and the like.

[0018] In a further embodiment, the wall of the capsule has a steampermeability of less than 1.3×10⁻¹⁴ kg/(m² s Pa), preferably of1.5×10⁻¹⁶ to 2×10⁻¹⁶ kg/(m² s Pa). The advantage of this feature is thatthe contents of the capsule are also protected from water ingeographical zones with high air humidity.

[0019] In preferred embodiments, the synthetic material is polyethylene,especially polyethylene with a density of between 9000 and 10,000 kg/m³,preferably 9600 kg/m³ (high-density polyethylene), polycarbonate,polyester, polypropylene or polyethyleneterephthalate.

[0020] In a preferred embodiment, the cap and the body have the shape ofa cylinder with a round cross-section and a convex, practicallyhemispherical closed underside, and both consist of high-densitypolyethylene with a density of between 9500 and 10000 kg/m³.

[0021] The capsules according to the invention can be used in all kindsof powder inhalers where the preparation which is to be inhaled isadministered by means of a capsule.

[0022] In a preferred embodiment, the cap and body of the capsule are ofmutually-similar cylindrical shape, comprising an inherently closedjacket with, in each case, a closed end and an open end. Here, the shapeand size of the cap and the capsule are such that the body can be pushedtelescopically into the open end of the cap with its open end, so thatthe cap is attached solidly to the body.

[0023] In a special embodiment, the cap and body are provided withlocking devices, which are advantageous for temporary and/or finalclosure of the capsule.

[0024] In such an embodiment, there are point-shaped elevations on theinner jacket of the cap and on the outer jacket of the body there aresomewhat larger point-shaped recesses which are arranged so that theelevations engage with the recesses on closure of the capsule.Alternatively, the elevations can be located on the outer jacket of thebody and the recesses on the inner jacket of the cap. Arrangements arepreferred where the elevations or recesses are respectively disposed ina ring or spiral shape about the jacket. Instead of the point-shapeddesign of the elevations and recesses, these can also run continuouslyaround the cap or the body in a ring-shape.

[0025] In one embodiment, one or more elevations, running annularlyaround the inner jacket of the cap and the outer jacket of the body, aredesigned so that elevations on the cap are each positioned next to anelevation of the body when the capsule is closed.

[0026] In embodiments with the aforementioned annular recesses and/orelevations, these can be continuous or interrupted.

[0027] In a further embodiment, elevations are formed on the outside ofthe body near the open end and holes are formed in the cap near the openend so that the elevations of the body locate into the holes in the capwhen the capsule is closed. The elevations can be designed so that thecap can be opened at any time without damage to the capsule, or so thatonce closed, the capsule can no longer be opened without being damaged.

[0028] In a further embodiment, a bulge is designed on the outer side ofthe body, which runs around the body perpendicular to the connectingaxis between the cap and the body. The bulge serves as a stopper for thecapsule when this is placed over the body, in order to prevent piercingof the cap with the body. The area between the open end of the body andthe bulge corresponds to the area of the body over which the cap can bepushed. The bulge is located on the body so that the cap can be pushedfar enough over the body to ensure good attachment between the cap andthe body. That is, the bulge may not, for example, be located directlyon the open side of the body. The side of the bulge which faces the openend of the body stands as a vertical edge on the outer wall of the bodyso that the cap cannot be pushed over the bulge on closure. The side ofthe bulge which faces towards the closed end of the body can be designedin the form of an almost right-angled edge or can taper towards theclosed end of the body. The formation of a practically right-angled edgecan be advantageous where the capsule fits loosely into the capsuleholder, whilst the version with the tapering bulge can be advantageousin the case of a tight fit. The bulge can be continuous or interrupted.

[0029] In a preferred embodiment, the bulge tapers continuously to theclosed end of the body and stands with its end oriented towards the openend of the body perpendicularly on the capsule body. The height of theedge thus formed is such that, in the closed position of the capsule,the edge does not project beyond the cap, thus providing a flattransition from the cap to the body.

[0030] The thickness of the walls of the cap and the body can vary overthe entire area. Thus, the wall thickness is generally greater in therounded areas of the cap or the body, or at that point in the body wherethe bulge is formed, than in the areas where the walls run straight. Inone embodiment, the walls of the cap and the body have a thickness of0.1 to 0.5 mm.

[0031] In one possible embodiment, knobs are formed on the outside ofthe capsule, and in another embodiment there are three or more ribs,which run parallel to the longitudinal axis of the capsule. Theadvantage of these devices is that the capsule can be removed from acapsule holder e.g. as used in the aforementioned powder inhalers, insuch a way that it does not get damaged or break open. The ribs or theknobs can run around the entire outside of the capsule or may only covera part thereof. Alternatively, they may only be provided on the cap oronly in the area of the body which is visible from outside in its closedstate. The ribs run parallel to the longitudinal axis of the capsule andensure that the capsule is fixed vertically in the aforementionedcapsule holder. In the case of the capsule having a circularcross-section, the ribs are preferably arranged so that thecross-section of the capsule does not have rotational symmetry about itscentral axis. In such an embodiment, the ribs may be provided only inthe area of the body which is visible when the capsule is closed. Thisembodiment prevents the capsule jamming in a capsule holder. In anembodiment without a bulge but with ribs on the part of the body whichis visible when the capsule is closed, the ribs are designed so that theends of the ribs which are orientated towards the open end of the bodyperform the function of the bulge, namely to act as a stopper for thecap, when the cap is attached to the body.

[0032] In a further embodiment, the jackets of the cap and the bodydescribe a hollow cylinder with a round, oval, triangular,quadrilateral, hexagonal, octagonal or polygonal cross-section, wherethe respective upper side is open and the underside is closed. Theclosed underside can be flat or convex. The angled embodiments have theadvantage that they can for example be stored in a more space-savingmanner than the round embodiments.

[0033] In one embodiment, the elongation of the capsule (distance fromthe closed end of the body to the closed end of the cap in relation tothe diameter when the capsule is closed) is greater than 1, in oneembodiment the elongation is 1 and in yet another embodiment theelongation is smaller than 1. The latter has the advantage that the bodyhas a larger opening for filling.

[0034] In one of the embodiments with an elongation of 1, the cap andthe body are designed so that the closed capsule is spherical, which canbe advantageous for automatic loading of a powder inhaler with thecapsule from a reservoir.

[0035] In order to attain better sealing between the cap and the bodywhen the filled capsules are closed, the joint between the cap and thebody can be welded, adhesively bonded or wrapped, thus reducing thesteam permeability to as little as a tenth. Alternatively, the entirecap can be covered with a protective film.

[0036] In another preferred embodiment, the gap may be sealed with afiller. Suitable fillers for filling the gap in this way are thepharmaceutically acceptable fillers such as Eudragit. A filler of thiskind can be inserted in the gap as a solution or suspension in asuitable, preferably highly volatile solvent. Suitable solvents includefluorochlorohydrocarbons such as methylene chloride or chloroform,fluorohydrocarbons, alcohols such as methanol, ethanol, propanol,isopropanol, alkanes such as propane, hexane, heptane, ketones such asacetone, esters such as ethyl acetate, ethers such as dimethylether ordiethylether or other liquids known from the prior art to be suitablefor solutions or suspensions, especially volatile liquids and thosewhich do not attack the capsule material, do not interact chemicallywith pharmaceutical compositions or alter their bioavailability. Thesolution or suspension with the filler must be of a nature andconcentration such that the solution or suspension delivers sufficientfiller into the gap so that, after the solvent has evaporated, thefiller left behind provides a tight seal and at the same time thesolution or suspension should not be of a nature and concentration suchthat it is too viscous to penetrate into the gap or be drawn into it bycapillary action.

[0037] Preferably, a solution of Eudragit and acetone is used to sealthe gap.

[0038] It can be seen from the description that the capsule, accordingto the invention, is suitable for holding any kind of powderedpharmaceutical preparation which is suitable for inhalation. In aspecial application, the capsule contains cromoglycic acid, reproterol,beclomethasone, terbutaline, salbutamol, salmeterol, ketotifen,orciprenaline, fluticasone, insulin, ipratropium, dexamethasone,bambuterol, tiotropium, budesonide, fenoterol, clenbuterol,prednisolone, prednisone, prednylidene, methylprednisolone, formoterol,nedocromil, the salts or mixtures thereof or another cortisonepreparation or atropine derivative suitable for inhalation purposes.

[0039] In a preferred embodiment, the capsule contains ipratropiumbromide or tiotropium bromide.

DESCRIPTION OF THE DIAGRAMS

[0040] The diagrams show various embodiments of the capsule according tothe invention by way of example, but only serve to illustrate theinvention without restricting its scope.

[0041]FIG. 1 shows the simplest embodiment of the capsules according tothe invention in lateral cross-section.

[0042]FIGS. 2a and 2 b each show a different embodiment of the capsulewith a tapering bulge on the body in lateral cross-section.

[0043]FIG. 3 shows an embodiment of the capsule with an angular bulge onthe body in lateral cross-section.

[0044]FIG. 4 shows an embodiment of the capsule with a tapering bulge onthe body and annular recess on the body and cap in lateralcross-section.

[0045]FIG. 5 shows an embodiment of the capsule with tapering bulge onthe body and annular recess on the body and cap in frontal view.

[0046]FIG. 6 shows an embodiment of the capsule with tapering bulge onthe body and point-shaped recesses or elevations on the body and cap infrontal view.

[0047]FIG. 7 shows an embodiment of the capsule with tapering bulge onthe body and point-shaped elevations on the body and point-shaped holesin the cap in frontal view.

[0048]FIG. 8 shows an embodiment of the capsule with ribs on the body infrontal view.

[0049]FIG. 9 shows the capsule of FIG. 7 in horizontal cross-section.

[0050]FIGS. 10a, 10 b and 10 c show embodiments of the capsule, eachwith a different cross-section.

[0051] An embodiment illustrating a spherical capsule is not shown.

[0052] In FIG. 1, the simplest embodiment of the capsule according tothe invention 1 is shown in cross-section. The capsule 1 consists of thecap 2 and the body 3, which are fitted telescopically one into theother. The cap 2 and the body 3 are of the same shape and each has aconvex underside 4.

[0053]FIG. 2a shows a cross-section of an embodiment where a bulge 5 isformed on the body 3 of the capsule 1, this bulge tapering towards theclosed end of the body. The bulge 5 stands practically vertically on thebody with its side orientated towards the open end of the body. The edgethus formed demarcates the area of the body over which the cap 2 can bepushed telescopically.

[0054] Another embodiment is shown in FIG. 2b. The cross-section showsthat this embodiment differs from that shown in FIG. 2a in that the wallthickness of the cap 2 or the body 3 is not uniformly great over theentire area, but rather varies over individual partial areas. Inaddition, the convex undersides 4 of the cap or the body each have aconcave indentation at the vertex.

[0055] In FIG. 3 an embodiment is represented where the bulge 5 sits onthe body almost at right angles to the upper side of the body and alsothe underside of the body. The embodiment of FIG. 4 represents a furtherdevelopment of the embodiment of FIG. 2a, where an annular recess 6 or 7is formed in cap 2 or body 3 in order to close the capsule 1 moresatisfactorily.

[0056]FIG. 5 shows a front view of the embodiment shown in FIG. 4 as across-section.

[0057]FIG. 6 shows a further variant of the invention with point-shapedrecesses 8 and 9 in front view.

[0058] In FIG. 7, a variant of the capsule 1 is shown where elevations10 are provided on the body 3 near the open end, and holes 11 areprovided in the cap 2 near the open end so that the elevations 10 engagewith the holes 11 when the capsule is closed.

[0059]FIG. 8 shows an embodiment of the capsule 1 from outside, whereribs 12 are provided on the body 3.

[0060]FIG. 9 shows the body 3 of the embodiment in FIG. 7 incross-section. The cross-section shows that the three ribs 12 are notarranged with rotational symmetry about the central axis of the body.FIGS. 10a, 10 b and 10 c show a capsule 1 of quadrilateral, triangularand octagonal cross-section, respectively.

What is claimed is:
 1. A capsule to hold a pharmaceutical preparationfor powder inhalation which comprises a capsule body and a capsule cap,which are to be attached to one another so as to form a stable, enclosedhollow space of defined volume, the capsule body and the capsule cap,being made of a water-insoluble, hydrophobic synthetic material.
 2. Thecapsule according to claim 1 , characterized in that the walls of thecap and the body are 0.1 mm to 0.5 mm thick.
 3. The capsule according toclaim 1 , characterized in that the capsule can withstand a force actingupon its longitudinal axis and its transverse axis of up to 15 N.
 4. Thecapsule according to claim 1 , characterized in that the Shore hardnessD of the synthetic material is in the range from 65 to
 73. 5. Thecapsule according to claim 1 , characterized in that the wall of thecapsule has a steam permeability of less than 1.3×10⁻¹⁴ kg/(m²s Pa). 6.The capsule according to claim 5 , characterized in that the wall of thecapsule has a steam permeability of 1.5×10⁻¹⁶ to 2×10⁻¹⁶ kg/(m²s Pa). 7.The capsule according to claim 1 , characterized in that the syntheticmaterial is polyethylene, polycarbonate, polyester, polypropylene orpolyethyleneterephthalate.
 8. The capsule according to claim 7 ,characterized in that the synthetic material is polyethylene with adensity of 9,000-10,000 kg/m³.
 9. The capsule according to claim 1 ,characterized in that one or more elevations or recesses are located onthe inner jacket of the cap and one or more recesses or elevations arelocated on the outer jacket of the body, these elevations or recessesbeing arranged so that the elevations engage with the recesses when thecapsule is closed, by attaching the capsule body and the capsule cap.10. The capsule according to claim 1 , characterized in that a bulgeruns in an annular shape around the outside of the body perpendicular tothe connecting axis of the cap and the body, the side of the bulge whichis orientated towards the open end of the body standing practically atright angles to the outer wall of the body.
 11. The Capsule according toclaim 1 , characterized in that the capsule body and capsule cap areboth made of high density polyethylene and are both in the shape of acylinder of round cross section with a convex closed end, so that theelongation of the capsule (distance from the closed end of the body tothe closed end of the cap in relation to the diameter when the capsuleis closed) is greater than
 1. 12. The capsule according to claim 12 ,characterized in that the joint between the body and cap, or the gap, issealed by welding, adhesive bonding, wrapping or covering the cap with aprotective film.
 13. The capsule according to claims 12, characterizedin that the joint between the body and cap, or the gap, is sealed byfilling with a pharmaceutically acceptable filler.
 14. The capsuleaccording to claim 13 , characterized in that the filler is Eudragit.15. The capsule according to claim 1 which further comprises in theenclosed hollow space a pharmaceutical preparation comprisingcromoglycic acid, reproterol, beclomethasone, terbutaline, albeterol,salmeterol, ketotifen, orciprenaline, fluticasone, ipratropium,dexamethasone, bambuterql, tiotropium, budesonide, fenoterol,clenbuterol, prednisolone, prednisone, prednylidene, methylprednisolone,formoterol, nedocromil, insulin,ipratropium bromide, tiotropium bromide,a salt thereof or a mixture thereof or another cortisone preparation oratropine derivative, which pharmaceutical preparation is suitable forinhalation.